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Comparison of CpG Island Methylator Phenotype (CIMP) Frequency in Colon Cancer Using Different Probe- and Gene-Specific Scoring Alternatives on Recommended Multi-Gene Panels

BACKGROUND: In colorectal cancer a distinct subgroup of tumours demonstrate the CpG island methylator phenotype (CIMP). However, a consensus of how to score CIMP is not reached, and variation in definition may influence the reported CIMP prevalence in tumours. Thus, we sought to compare currently su...

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Autores principales: Berg, Marianne, Hagland, Hanne R., Søreide, Kjetil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897740/
https://www.ncbi.nlm.nih.gov/pubmed/24466191
http://dx.doi.org/10.1371/journal.pone.0086657
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author Berg, Marianne
Hagland, Hanne R.
Søreide, Kjetil
author_facet Berg, Marianne
Hagland, Hanne R.
Søreide, Kjetil
author_sort Berg, Marianne
collection PubMed
description BACKGROUND: In colorectal cancer a distinct subgroup of tumours demonstrate the CpG island methylator phenotype (CIMP). However, a consensus of how to score CIMP is not reached, and variation in definition may influence the reported CIMP prevalence in tumours. Thus, we sought to compare currently suggested definitions and cut-offs for methylation markers and how they influence CIMP classification in colon cancer. METHODS: Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), with subsequent fragment analysis, was used to investigate methylation of tumour samples. In total, 31 CpG sites, located in 8 different genes (RUNX3, MLH1, NEUROG1, CDKN2A, IGF2, CRABP1, SOCS1 and CACNA1G) were investigated in 64 distinct colon cancers and 2 colon cancer cell lines. The Ogino gene panel includes all 8 genes, in addition to the Weisenberger panel of which only 5 of the 8 genes included were investigated. In total, 18 alternative combinations of scoring of CIMP positivity on probe-, gene-, and panel-level were analysed and compared. RESULTS: For 47 samples (71%), the CIMP status was constant and independent of criteria used for scoring; 34 samples were constantly scored as CIMP negative, and 13 (20%) consistently scored as CIMP positive. Only four of 31 probes (13%) investigated showed no difference in the numbers of positive samples using the different cut-offs. Within the panels a trend was observed that increasing the gene-level stringency resulted in a larger difference in CIMP positive samples than increasing the probe-level stringency. A significant difference between positive samples using ‘the most stringent’ as compared to ‘the least stringent’ criteria (20% vs 46%, respectively; p<0.005) was demonstrated. CONCLUSIONS: A statistical significant variation in the frequency of CIMP depending on the cut-offs and genes included in a panel was found, with twice as many positives samples by least compared to most stringent definition used.
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spelling pubmed-38977402014-01-24 Comparison of CpG Island Methylator Phenotype (CIMP) Frequency in Colon Cancer Using Different Probe- and Gene-Specific Scoring Alternatives on Recommended Multi-Gene Panels Berg, Marianne Hagland, Hanne R. Søreide, Kjetil PLoS One Research Article BACKGROUND: In colorectal cancer a distinct subgroup of tumours demonstrate the CpG island methylator phenotype (CIMP). However, a consensus of how to score CIMP is not reached, and variation in definition may influence the reported CIMP prevalence in tumours. Thus, we sought to compare currently suggested definitions and cut-offs for methylation markers and how they influence CIMP classification in colon cancer. METHODS: Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), with subsequent fragment analysis, was used to investigate methylation of tumour samples. In total, 31 CpG sites, located in 8 different genes (RUNX3, MLH1, NEUROG1, CDKN2A, IGF2, CRABP1, SOCS1 and CACNA1G) were investigated in 64 distinct colon cancers and 2 colon cancer cell lines. The Ogino gene panel includes all 8 genes, in addition to the Weisenberger panel of which only 5 of the 8 genes included were investigated. In total, 18 alternative combinations of scoring of CIMP positivity on probe-, gene-, and panel-level were analysed and compared. RESULTS: For 47 samples (71%), the CIMP status was constant and independent of criteria used for scoring; 34 samples were constantly scored as CIMP negative, and 13 (20%) consistently scored as CIMP positive. Only four of 31 probes (13%) investigated showed no difference in the numbers of positive samples using the different cut-offs. Within the panels a trend was observed that increasing the gene-level stringency resulted in a larger difference in CIMP positive samples than increasing the probe-level stringency. A significant difference between positive samples using ‘the most stringent’ as compared to ‘the least stringent’ criteria (20% vs 46%, respectively; p<0.005) was demonstrated. CONCLUSIONS: A statistical significant variation in the frequency of CIMP depending on the cut-offs and genes included in a panel was found, with twice as many positives samples by least compared to most stringent definition used. Public Library of Science 2014-01-21 /pmc/articles/PMC3897740/ /pubmed/24466191 http://dx.doi.org/10.1371/journal.pone.0086657 Text en © 2014 Berg et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Berg, Marianne
Hagland, Hanne R.
Søreide, Kjetil
Comparison of CpG Island Methylator Phenotype (CIMP) Frequency in Colon Cancer Using Different Probe- and Gene-Specific Scoring Alternatives on Recommended Multi-Gene Panels
title Comparison of CpG Island Methylator Phenotype (CIMP) Frequency in Colon Cancer Using Different Probe- and Gene-Specific Scoring Alternatives on Recommended Multi-Gene Panels
title_full Comparison of CpG Island Methylator Phenotype (CIMP) Frequency in Colon Cancer Using Different Probe- and Gene-Specific Scoring Alternatives on Recommended Multi-Gene Panels
title_fullStr Comparison of CpG Island Methylator Phenotype (CIMP) Frequency in Colon Cancer Using Different Probe- and Gene-Specific Scoring Alternatives on Recommended Multi-Gene Panels
title_full_unstemmed Comparison of CpG Island Methylator Phenotype (CIMP) Frequency in Colon Cancer Using Different Probe- and Gene-Specific Scoring Alternatives on Recommended Multi-Gene Panels
title_short Comparison of CpG Island Methylator Phenotype (CIMP) Frequency in Colon Cancer Using Different Probe- and Gene-Specific Scoring Alternatives on Recommended Multi-Gene Panels
title_sort comparison of cpg island methylator phenotype (cimp) frequency in colon cancer using different probe- and gene-specific scoring alternatives on recommended multi-gene panels
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897740/
https://www.ncbi.nlm.nih.gov/pubmed/24466191
http://dx.doi.org/10.1371/journal.pone.0086657
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